This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent studies suggest a link between neuropsychiatric disorders and HIV/SIV infection. Most evidence indicates monocytes/macrophages are the primary cell type infected within the CNS and that they contribute to CNS inflammation and neurologic disease. Substance P (SP), a pleotropic neuropeptide implicated in inflammation, depression and immune modulation via interaction with its cognate receptor, the neurokinin 1 receptor (NK1-R), is produced by monocyte/macrophages. While the presence of NK1-R on neurons is well known, its role on cells of the immune system such as monocyte/macrophages is just beginning to emerge. Therefore, we have examined the expression of SP and NK1-R and their relationship to SIVE lesions and SIV-infected cells. These studies demonstrated that the expression of SP and NK1-R is significantly increased in SIVE lesions. Macrophages are the principal cell expressing NK1-R in these lesions. All of the SIV-infected macrophages expressed NK1-R. Additionally, we examined the functional role of SP as a proinflammatory mediator of monocyte activation and chemotaxis. The treatment of monocytes with SP elicited changes in cell-surface expression for CCR5 and NK1-R in a dose-dependent manner. Treatment with SP enhanced both SP and CCL5 mediated chemotaxis. Taken together, these observations suggest that the role of SP and NK1-R are important in SIV infection of macrophages and the development of SIVE lesions.